Clinical characteristics.

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported.

The three autosomal dominant neuromuscular disorders (mildest to most severe) are:

• Charcot-Marie-Tooth disease type 2C
• Scapuloperoneal spinal muscular atrophy
• Congenital distal spinal muscular atrophy

The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures.

The six autosomal dominant skeletal dysplasias (mildest to most severe) are:

• Familial digital arthropathy-brachydactyly
• Autosomal dominant brachyolmia
• Spondylometaphyseal dysplasia, Kozlowski type
• Spondyloepiphyseal dysplasia, Maroteaux type
• Parastremmatic dysplasia
• Metatropic dysplasia

The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened.

Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

Diagnosis/testing.

The diagnosis of an autosomal dominant TRPV4 disorder is established in a proband with characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. SNHL is managed by specialists to determine the best management options.

• For neuromuscular disorders, neuropathy and respiratory dysfunction are managed in a routine manner; individuals with laryngeal dysfunction require ENT evaluation that should include speech therapy, laryngoscopy, and, in some instances, surgery.
• For skeletal dysplasias, physical therapy/exercise and heel-cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present.

Surveillance: For neuromuscular disorders, annual neurologic examinations, physical therapy assessments, ENT monitoring of laryngeal function, dynamic breathing chest x-ray, and hearing assessment. For skeletal dysplasias, annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia; annual hearing assessment.

Agents/circumstances to avoid: For neuromuscular disorders, obesity, as it makes walking more difficult; diabetes; medications that are toxic or potentially toxic to persons with a peripheral neuropathy. For skeletal dysplasias, extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints.

Pregnancy management: Ideally a woman with TRPV4 disorder would seek consultation from a high-risk OB-GYN or maternal-fetal medicine specialist to evaluate risk associated with pregnancy and delivery.

Genetic counseling.

TRPV4 disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an autosomal dominant TRPV4 disorder have an affected parent. However, since the most severe skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes likely have a de novo pathogenic variant and unaffected parents. Each child of an individual with an autosomal dominant TRPV4 disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of reduced penetrance and variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have the same phenotype as the parent. Prenatal and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of an autosomal dominant TRPV4 disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in TRPV4 identified by molecular genetic testing (see Table 3).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous TRPV4 variant of uncertain significance does not establish or rule out the diagnosis.

Single-gene testing. Sequence analysis of TRPV4 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: (1) Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. (2) To date, a large TRPV4 deletion or duplication has not been reported in an individual with an autosomal dominant TRPV4 disorder.

A multigene panel that includes TRPV4 and other genes of interest (see Differential Diagnosis) can be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

The two groups of disorders and the phenotypes comprising autosomal dominant TRPV4 disorders (listed from mildest to most severe) are:

• Neuromuscular disorders (see Table 1):
  • Charcot-Marie-Tooth disease type 2C
  • Scapuloperoneal spinal muscular atrophy
  • Congenital distal spinal muscular atrophy
• Skeletal dysplasias (see Table 2):
  • Familial digital arthropathy-brachydactyly
  • Autosomal dominant brachyolmia
  • Spondylometaphyseal dysplasia, Kozlowski type
  • Spondyloepiphyseal dysplasia, Maroteaux type
  • Parastremmatic dysplasia
  • Metatropic dysplasia

The phenotypic spectra within both neuromuscular and skeletal groups are broad and overlapping, and the phenotypes of both groups can in rare cases overlap as well [Chen et al 2010, Unger et al 2011, Cho et al 2012].

Of note, sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate, can occur in both phenotypes. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010].

Genotype-Phenotype Correlations

In general, specific sets of TRPV4 pathogenic variants have been associated with either neuromuscular disorders or skeletal dysplasia; overlap may occur, however, making genotype-phenotype correlations difficult (see Molecular Genetics) [Unger et al 2011, Sullivan & Earley 2013].

Functional studies suggest that TRPV4 pathogenic variants associated with neuromuscular disorders and skeletal dysplasias may cause a gain-of-channel function [Rock et al 2008, Krakow et al 2009, Nilius & Voets 2013, Sullivan et al 2015], whereas the pathogenic variants associated with familial digital arthropathy-brachydactyly (FDAB) may cause a loss-of-channel function.

TRPV4 neuromuscular disorders. Several studies suggest that most TRPV4 pathogenic variants associated with a neuromuscular phenotype cluster on the highly positively charged convex surface of the ankyrin repeats domain and target arginine residues that are strictly conserved throughout 27 available TRPV4 orthologs [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Sullivan et al 2015]. These surface pathogenic variants are located in three consecutive finger loops of the protein, a distinct region of the TRPV4 ankyrin repeats. The most commonly reported and best validated pathogenic TRPV4 variants are the following: p.Arg186Gln, p.Arg232Cys, p.Arg269Cys, p.Arg269His, p.Arg315Trp, p.Arg316Cys, and p.Arg316His [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Klein et al 2011, Landouré et al 2012]. Variable phenotypes have been reported, even among members of the same family [Landouré et al 2010].

TRPV4 skeletal dysplasias. In total, more than 50 pathogenic variants in TRPV4 have been reported to cause brachyolmias. While the pathogenic variants are spread throughout the gene, two hot spots have been observed at residues Pro799 in exon 15 and Arg594 in exon 11 [Nishimura et al 2012], which localize to the channel pore region.

The familial digital arthropathy-brachydactyly-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (pathogenic variants p.Gly270Val, p.Arg271Pro, p.Phe273Leu) [Nilius & Voets 2013].

Overlap of TRPV4 neuromuscular disorders and skeletal dysplasias. Of note, the pathogenic variants p.Ala217Ser, p.Glu278Lys, p.Arg269Cys, p.Arg315Trp, p.Tyr591Cys, p.Arg594His, p.Val620Ile, p.Glu797Lys, and p.Pro799Arg have been associated with both neuromuscular disease and skeletal dysplasia [Zimoń et al 2010, Cho et al 2012, Faye et al 2019]. In addition, the pathogenic variant p.Ser542Tyr caused both CMT2C and short stature in one family [Chen et al 2010].

Penetrance

Autosomal dominant TRPV4 neuromuscular disorders. Penetrance is reduced with the neuromuscular disease-associated pathogenic variants.

Autosomal dominant TRPV4 skeletal dysplasias. In contrast, penetrance of the skeletal dysplasia phenotype appears to be high; however, intra- and interfamilial variability is significant [Dai et al 2010].

Nomenclature

Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C.

Spondyloepiphyseal dysplasia, Maroteaux type is also referred to as pseudo-Morquio syndrome type 2.

Prevalence

The prevalence of the autosomal dominant TRPV4 neuromuscular and skeletal dysplasias has not been well studied.

Fawcett et al [2012] determined that 13 (<1%) of 422 individuals with a CMT2 (axonal CMT) phenotype were heterozygous for a TRPV4 pathogenic variant. Of note, the detection of a TRPV4 pathogenic variant increased to between 9% and 16% in those with a CMT2 phenotype with additional unusual features (e.g., vocal fold weakness, diaphragmatic paresis, skeletal dysplasia) [Fawcett et al 2012, Echaniz-Laguna et al 2014].

Autosomal Dominant TRPV4 Neuromuscular Disorders

Autosomal dominant TRPV4 neuromuscular disorders (Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy) resemble several other disorders (see Table 4).

Note: See Charcot-Marie-Tooth Hereditary Neuropathy Overview for a general overview of CMT2.

Autosomal Dominant TRPV4 Skeletal Dysplasias

Autosomal dominant TRPV4 skeletal dysplasias have a broad phenotypic spectrum and, thus, many skeletal dysplasias to consider in the differential diagnosis.

Mild (familial digital arthropathy-brachydactyly). The differential diagnosis includes reactive arthropathy, diabetic arthropathy, and other forms of brachydactyly [Amor et al 2002].

Intermediate (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; and spondyloepiphyseal dysplasia, Maroteaux type) and severe (parastremmatic dysplasia and metatropic dysplasia). See Table 5.

Brachyolmia types 1 and 2 (OMIM 271530 and 613678) can also be considered in the differential diagnosis of intermediate autosomal dominant TRPV4 skeletal dysplasias. The molecular basis of these disorders is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4 neuromuscular disorder, the evaluations summarized in Table 6a (if not performed as part of the evaluation that led to the diagnosis) are recommended.

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4 skeletal dysplasia, the evaluations summarized in Table 6b (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, ENT specialists, and physical and occupational therapists.

Surveillance

Agents/Circumstances to Avoid

In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both

For neuromuscular disorders. Preventive health care to avoid diabetes-related complications is recommended. Neurotoxic medications should be avoided. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. See also the Inherited Neuropathy Consortium website for additional information.

For skeletal dysplasias

• In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
• Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no registry or data regarding the frequency or outcome of pregnancies in women with a TRPV4-related disorder; however, the following general information may be reasonable to consider. Ideally a woman with an autosomal dominant TRPV4 disorder would seek consultation from a high-risk OB-GYN or maternal-fetal medicine specialist to evaluate her risks for pregnancy and delivery. Increased risk of ectopic pregnancy has been reported [Li et al 2019].

Autosomal dominant TRPV4 neuromuscular disorders. Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMTs. About 50% of women with CMT described increased weakness during pregnancy that usually resolved post partum [Rudnik-Schöneborn et al 1993]. Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] described the obstetric approach to women with mild and severe forms of CMT. Brock et al [2009] describe use of anesthesia during delivery in a single case study, indicating that regional management is the preferred and safer method, compared to general anesthesia. A German study reviewed 63 pregnancies in 33 women with CMT [Awater et al 2012] and found no increase in the frequency of cesarean section, forceps delivery, premature birth, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent.

Autosomal dominant TRPV4 skeletal dysplasias. In autosomal dominant TRPV4 skeletal dysplasias, the degree of pulmonary compromise (from the short trunk and decreased lung capacity) may affect the ability to carry a pregnancy to term. Thus, it is unlikely that a woman with metatropic dysplasia could carry a pregnancy. Pregnant women with a TRPV4 skeletal dysplasia generally undergo cesarean section delivery because of the small size of the pelvis.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Mathis et al [2015] have reviewed the future of therapeutic options in CMT.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet and orthopedic involvement.

Mode of Inheritance

TRPV4 neuromuscular and skeletal disorders caused by a heterozygous TRPV4 pathogenic variant are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Because the most severe TRPV4 skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes typically have a de novo pathogenic variant and unaffected parents.
• Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a TRPV4 pathogenic variant inherited from a heterozygous parent. (Note: A heterozygous parent may appear asymptomatic or have more or less severe clinical manifestations than the proband; see Penetrance and Genotype-Phenotype Correlations.) De novo variants have also been described in individuals with these phenotypes.
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing indicates that neither parent has the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

• If a parent of the proband is affected and/or is known to have the TRPV4 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• The specific phenotype, age of onset, and disease severity cannot be predicted accurately in a sib who inherits a familial pathogenic variant because of reduced penetrance and variable expressivity. A heterozygous sib may have the same phenotype as the proband or have less severe or more severe clinical manifestations (see Penetrance and Genotype-Phenotype Correlations).
• If the TRPV4 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TRPV4 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for a TRPV4 disorder because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with a TRPV4 disorder has a 50% chance of inheriting the TRPV4 pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of reduced penetrance and variable expressivity.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a TRPV4 skeletal disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be distinct from those of the parents.
  If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TRPV4 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Genetic counseling is recommended when both parents have a skeletal dysplasia.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the TRPV4 pathogenic variant has been identified in an affected family member. If identified to have inherited a TRPV4 pathogenic variant, further clinical evaluation, electromyography/nerve conduction velocity testing, and/or skeletal survey may be appropriate. No treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of a TRPV4 disorder, it is appropriate to consider testing of symptomatic individuals regardless of age.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for an autosomal dominant TRPV4 disorder are possible. However, specific phenotype, age of onset, and/or disease severity cannot be reliably predicted based on the results of prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TRPV4 encodes a nonselective Ca2+-permeable cation channel that is predominantly expressed at the plasma membrane [Garcia-Elias et al 2014]. TRPV4 can be activated by a wide range of stimuli including hypo-osmolarity, heat, and mechanical stretch, as well as numerous endogenous (e.g., endocannabinoid anandamide, arachidonic acid) and synthetic compounds (4α-phorbol-12,13-didecanoate [4αPDD]) [Garcia-Elias et al 2014]. TRPV4 is broadly expressed and has diverse physiologic roles in different tissues types:

• Osmosensation and flow sensing in the kidney [Pochynyuk et al 2013]
• Endothelial barrier function in the vascular system [Villalta & Townsley 2013]
• Mechanosensation and nociception in the sensory nervous system [Suzuki et al 2003, Alessandri-Haber et al 2009]
• Stretch sensation in the bladder [Gevaert et al 2007]
• Skin barrier function [Kida et al 2012]
• Chondrogenesis [Muramatsu et al 2007]
• Bone homeostasis [Masuyama et al 2012]
• Regulation of adipose oxidative metabolism [Ye et al 2012]

While the precise mechanisms of pathogenesis in TRPV4 disorders are not completely understood, the preponderance of evidence suggests that pathogenic variants cause toxicity through gain of ion channel function [Nilius & Voets 2013]. Given the incredibly diverse signaling pathways regulated by intracellular calcium influx, many possible downstream pathologic events are conceivable, including activation of calcium-sensitive proteases (such as calpains) or kinases (such as CaMKII), alterations in calcium-sensitive transcriptional programs, disruption of axonal transport, dysregulation of cytoskeletal remodeling, and altered neuronal excitability, among others. In addition, the downstream consequences of TRPV4 gain-of-channel function are likely to be dependent on cell type- and tissue-specific factors.

Mechanism of disease causation. TRPV4 disorders are diverse, but are likely linked through gain of TRPV4 ion channel function with tissue-specific downstream consequences. Notably, the vast majority of pathogenic variants reported are missense variants.

• Neuromuscular disorders. Gain of ion channel function, potentially via altered gating properties or altered responsiveness to activating stimuli has been proposed. The majority of disease variants causing neuromuscular disorders result in increased calcium influx in vitro [Deng et al 2010, Landouré et al 2010, Klein et al 2011, Sullivan et al 2015], and a Drosophila model of TRPV4 neuropathy demonstrated several neurologic phenotypes that could be ameliorated by genetic or pharmacologic inhibition of TRPV4 ion channel activity [Woolums et al 2020].
  The p.Arg186Gln, p.Arg237Leu, p.Arg269His, p.Arg269Cys, p.Arg316Cys, p.Arg316His, and p.Arg232Cys pathogenic variants showed increased ion channel activity resulting in intracellular calcium levels in vitro, and p.Arg269Cys led to increased intracellular calcium in vivo [Deng et al 2010, Landouré et al 2010, Klein et al 2011, Sullivan et al 2015, Woolums et al 2020].
• Skeletal dysplasias. The vast majority of skeletal dysplasia pathogenic variants are missense variants that are believed to cause gain of function, although frameshift and deletion variants have been reported [Dai et al 2010, Nishimura et al 2010]. Like pathogenic variants associated with neuromuscular disorders, skeletal dysplasia-associated variants also generally cause increased basal calcium influx [Loukin et al 2011]. The precise downstream pathogenic events remain unknown, although excessive inhibition of bone morphogenic protein with resultant impairment in endochondral ossification has been proposed based on in vitro studies and a knock-in mouse model [Leddy et al 2014a, Leddy et al 2014b].

Revision History

• 17 September 2020 (sw) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 30 July 2013 (as) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 11-1-22.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 11-1-22.

Literature Cited

• Alessandri-Haber N, Dina OA, Chen X, Levine JD. TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci. 2009;29:6217–28. [PMC free article: PMC2726836] [PubMed: 19439599]
• Amor DJ, Tudball C, Gardner RJ, Lamandé SR, Bateman JF, Savarirayan R. Familial digital arthropathy-brachydactyly. Am J Med Genet. 2002;108:235–40. [PubMed: 11891693]
• Argov Z, de Visser M. What we do not know about pregnancy in hereditary neuromuscular disorders. Neuromuscul Disord. 2009;19:675–9. [PubMed: 19692244]
• Astrea G, Brisca G, Fiorillo C, Valle M, Tosetti M, Bruno C, Santorelli FM, Battini R. Muscle MRI in TRPV4-related congenital distal SMA. Neurology. 2012;78:364–5. [PubMed: 22291064]
• Auer-Grumbach M, Olschewski A, Papić L, Kremer H, McEntagart ME, Uhrig S, Fischer C, Fröhlich E, Bálint Z, Tang B, Strohmaier H, Lochmüller H, Schlotter-Weigel B, Senderek J, Krebs A, Dick KJ, Petty R, Longman C, Anderson NE, Padberg GW, Schelhaas HJ, van Ravenswaaij-Arts CM, Pieber TR, Crosby AH, Guelly C. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet. 2010;42:160–4. [PMC free article: PMC3272392] [PubMed: 20037588]
• Awater C, Zerres K, Rudnik-Schöneborn S. Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients. Eur J Obstet Gynecol Reprod Biol. 2012;162:153–9. [PubMed: 22459654]
• Berciano J, Baets J, Gallardo E, Zimon M, Garcia A, Lopez-Laso E, Combarros O, Infante J, Timmerman V, Jordanova A, De Jonghe P. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 arg269-to-cys mutation. J Neurol. 2011;258:1413–21. [PubMed: 21336783]
• Brock M, Guinn C, Jones M. Anesthetic management of an obstetric patient with Charcot-Marie-Tooth disease: a case study. AANA J. 2009;77:335–7. [PubMed: 19911641]
• Chen DH, Sul Y, Weiss M, Hillel A, Lipe H, Wolff J, Matsushita M, Raskind W, Bird T. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology. 2010;75:1968–75. [PMC free article: PMC3014233] [PubMed: 21115951]
• Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, Chae JH, Yoo WJ, Tanaka Y, Matsui Y, Takigami I, Monges S, Zabel B, Shimizu K, Nishimura G, Lausch E, Ikegawa S. TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patients. Am J Med Genet A. 2012;158A:795–802. [PubMed: 22419508]
• Dai J, Kim OH, Cho TJ, Schmidt-Rimpler M, Tonoki H, Takikawa K, Haga N, Miyoshi K, Kitoh H, Yoo WJ, Choi IH, Song HR, Jin DK, Kim HT, Kamasaki H, Bianchi P, Grigelioniene G, Nampoothiri S, Minagawa M, Miyagawa SI, Fukao T, Marcelis C, Jansweijer MC, Hennekam RC, Bedeschi F, Mustonen A, Jiang Q, Ohashi H, Furuichi T, Unger S, Zabel B, Lausch E, Superti-Furga A, Nishimura G, Ikegawa S. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J Med Genet. 2010;47:704–9. [PubMed: 20577006]
• DeLong R, Siddique T. A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features. Arch Neurol. 1992;49:905–8. [PubMed: 1520078]
• Deng H-X, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau H-J, Yang Y, Zhai H, Siddique N, Hedley-Whyte ET, DeLong R, Martina M, Dyck PJ, Siddique T. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42:165–9. [PMC free article: PMC3786192] [PubMed: 20037587]
• Donaghy M, Kennett R. Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy. J Neurol. 1999;246:552–5. [PubMed: 10463355]
• Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, Aronson AE. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol. 1994;35:608–15. [PubMed: 8179305]
• Echaniz-Laguna A, Dubourg O, Carlier P, Carlier RY, Sabouraud P, Péréon Y, Chapon F, Thauvin-Robinet C, Laforêt P, Eymard B, Latour P, Stojkovic T. Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. Neurology. 2014;82:1919–26. [PubMed: 24789864]
• Fawcett KA, Murphy SM, Polke JM, Wray S, Burchell VS, Manji H, Quinlivan RM, Zdebik AA, Reilly MM, Houlden H. Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls. J Neurol Neurosurg Psychiatry. 2012;83:1204–9. [PubMed: 22851605]
• Faye E, Modaff P, Pauli R, Legare J. Combined phenotypes of spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C secondary to a TRPV4 pathogenic variant. Mol Syndromol. 2019;10:154–60. [PMC free article: PMC6528083] [PubMed: 31191204]
• Garcia-Elias A, Mrkonjić S, Jung C, Pardo-Pastor C, Vicente R, Valverde MA. The TRPV4 channel. Handb Exp Pharmacol. 2014;222:293–319. [PubMed: 24756711]
• Gevaert T, Vriens J, Segal A, Everaerts W, Roskams T, Talavera K, Owsianik G, Liedtke W, Daelemans D, Dewachter I, Van Leuven F, Voets T, De Ridder D, Nilius B. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest. 2007;117:3453–62. [PMC free article: PMC2030459] [PubMed: 17948126]
• Greenwood JJ, Scott WE. Charcot-Marie-Tooth disease: peripartum management of two contrasting clinical cases. Int J Obstet Anesth. 2007;16:149–54. [PubMed: 17275278]
• Hoff JM, Gilhus NE, Daltveit AK. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease. Neurology. 2005;64:459–62. [PubMed: 15699375]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Kannu P, Aftimos S, Mayne V, Donnan L, Savarirayan R. Metatropic dysplasia: clinical and radiographic findings in 11 patients demonstrating long-term natural history. Am J Med Genet A. 2007;143A:2512–22. [PubMed: 17879966]
• Kida N, Sokabe T, Kashio M, Haruna K, Mizuno Y, Suga Y, Nishikawa K, Kanamaru A, Hongo M, Oba A, Tominaga M. Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes. Pflügers Arch. 2012;463:715–25. [PubMed: 22374181]
• Klein CJ, Shi Y, Fecto F, Donaghy M, Nicholson G, McEntagart ME, Crosby AH, Wu Y, Lou H, McEvoy KM, Siddique T, Deng HX, Dyck PJ. TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology. 2011;76:887–94. [PMC free article: PMC3059145] [PubMed: 21288981]
• Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009;84:307–15. [PMC free article: PMC2667978] [PubMed: 19232556]
• Landouré G, Sullivan JM, Johnson JO, Munns CH, Shi Y, Diallo O, Gibbs JR, Gaudet R, Ludlow CL, Fischbeck KH, Traynor BJ, Burnett BG, Sumner CJ. Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family. Neurology. 2012;79:192–4. [PMC free article: PMC3390542] [PubMed: 22675077]
• Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42:170–4. [PMC free article: PMC2812627] [PubMed: 20037586]
• Leddy HA, McNulty AL, Guilak F, Liedtke W. Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias. Rare Dis. 2014a;2:e962971. [PMC free article: PMC4755236] [PubMed: 26942100]
• Leddy HA, McNulty AL, Lee SH, Rothfusz NE, Gloss B, Kirby ML, Hutson MR, Cohn DH, Guilak F, Liedtke W. Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations. FASEB J. 2014b;28:2525–37. [PMC free article: PMC4021446] [PubMed: 24577120]
• Li C, Wu YT, Zhu Q, Zhang HY, Huang Z, Zhang D, Qi H, Liang GL, He XQ, Wang XF, Tang X, Huang HF, Zhang J. TRPV4 is involved in levonorgestrel-induced reduction in oviduct ciliary beating. J Pathol. 2019;248:77–87. [PMC free article: PMC6593834] [PubMed: 30632164]
• Loukin S, Su Z, Kung C. Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations. PLoS One. 2011;6:e19533. [PMC free article: PMC3088684] [PubMed: 21573172]
• Masuyama R, Mizuno A, Komori H, Kajiya H, Uekawa A, Kitaura H, Okabe K, Ohyama K, Komori T. Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass. J Bone Miner Res. 2012;27:1708–21. [PubMed: 22492541]
• Mathis S, Magy L, Vallat JM. Therapeutic options in Charcot-Marie-Tooth diseases. Expert Rev Neurother. 2015;15:355–66. [PubMed: 25703094]
• McEntagart ME, Reid SL, Irrthum A, Douglas JB, Eyre KE, Donaghy MJ, Anderson NE, Rahman N. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann Neurol. 2005;57:293–7. [PubMed: 15668982]
• Muramatsu S, Wakabayashi M, Ohno T, Amano K, Ooishi R, Sugahara T, Shiojiri S, Tashiro K, Suzuki Y, Nishimura R, Kuhara S, Sugano S, Yoneda T, Matsuda A. Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J Biol Chem. 2007;282:32158–67. [PubMed: 17804410]
• Nemec SF, Cohn DH, Krakow D, Funari VA, Rimoin DL, Lachman RS. The importance of conventional radiography in the mutational analysis of skeletal dysplasias (the TRPV4 mutational family). Pediatr Radiol. 2012;42:15–23. [PubMed: 21863289]
• Nilius B, Voets T. The puzzle of TRPV4 channelopathies. EMBO Rep. 2013;14:152–63. [PMC free article: PMC3566843] [PubMed: 23306656]
• Nishimura G, Dai J, Lausch E, Unger S, Megarbané A, Kitoh H, Kim OH, Cho TJ, Bedeschi F, Benedicenti F, Mendoza-Londono R, Silengo M, Schmidt-Rimpler M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A. Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am J Med Genet A. 2010;152A:1443–9. [PubMed: 20503319]
• Nishimura G, Lausch E, Savarirayan R, Shiba M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A, Unger S. TRPV4-associated skeletal dysplasias. Am J Med Genet C Semin Med Genet. 2012;160C:190–204. [PubMed: 22791502]
• Pochynyuk O, Zaika O, O'Neil RG, Mamenko M. Novel insights into TRPV4 function in the kidney. Pflügers Arch. 2013;465:177–86. [PMC free article: PMC3562383] [PubMed: 23207579]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, Vaglio A, Owsianik G, Janssens A, Voets T, Ikegawa S, Nagai T, Rimoin DL, Nilius B, Cohn DH. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008;40:999–1003. [PMC free article: PMC3525077] [PubMed: 18587396]
• Rudnik-Schöneborn S, Röhrig D, Nicholson G, Zerres K. Pregnancy and delivery in Charcot-Marie-Tooth disease type 1. Neurology. 1993;43:2011–6. [PubMed: 8413959]
• Santoro L, Manganelli F, Di Maio L, Barbieri F, Carella M, D'Adamo P, Casari G. Charcot-Marie-Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European family. Neuromuscul Disord. 2002;12:399–404. [PubMed: 12062259]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sullivan JM, Motley WW, Johnson JO, Aisenberg WH, Marshall KL, Barwick KE, Kong L, Huh JS, Saavedra-Rivera PC, McEntagart MM, Marion MH, Hicklin LA, Modarres H, Baple EL, Farah MH, Zuberi AR, Lutz CM, Gaudet R, Traynor BJ, Crosby AH, Sumner CJ. Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy. J Clin Invest. 2020;130:1506–12. [PMC free article: PMC7269582] [PubMed: 32065591]
• Sullivan JM, Zimanyi CM, Aisenberg W, Bears B, Chen DH, Day JW, Bird TD, Siskind CE, Gaudet R, Sumner CJ. Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy. Neurol Genet. 2015;1:e29. [PMC free article: PMC4811381] [PubMed: 27066566]
• Sullivan MN, Earley S. TRP channel Ca(2+) sparklets: fundamental signals underlying endothelium-dependent hyperpolarization. Am J Physiol Cell Physiol. 2013;305:C999–C1008. [PMC free article: PMC3840200] [PubMed: 24025865]
• Suzuki M, Mizuno A, Kodaira K, Imai M. Impaired pressure sensation in mice lacking TRPV4. J Biol Chem. 2003;278:22664–8. [PubMed: 12692122]
• Thibodeau ML, Peters CH, Townsend KN, Shen Y, Hendson G, Adam S, Selby K, Macleod PM, Gershome C, Ruben P, Jones SJM, Friedman JM, Gibson WT, Horvath GA, et al. Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy. Am J Med Genet A. 2017;173:3087–92. [PubMed: 28898540]
• Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, Di Stefano CM, Bertini E, Dionisi-Vici C, Nilius B, Zabel B, Superti-Furga A. Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy? Am J Med Genet A. 2011;155A:2860–4. [PubMed: 21964829]
• Velilla J, Marchetti MM, Toth-Petroczy A, Grosgogeat C, Bennett AH, Carmichael N, Estrella E, Darras BT, Frank NY, Krier J, Gaudet R, Gupta VA. Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis. Neurol Genet. 2019;5:e312. [PMC free article: PMC6454305] [PubMed: 31041394]
• Villalta PC, Townsley MI. Transient receptor potential channels and regulation of lung endothelial permeability. Pulm Circ. 2013;3:802–15. [PMC free article: PMC4070837] [PubMed: 25006396]
• Vlam L, Schelhaas HJ, van Blitterswijk M, van Vught PW, de Visser M, van der Kooi AJ, van der Pol WL, van den Berg LH. Mutations in the TRPV4 gene are not associated with sporadic progressive muscular atrophy. Arch Neurol. 2012;69:790–1. [PubMed: 22689196]
• Woolums BM, McCray BA, Sung H, Tabuchi M, Sullivan JM, Ruppell KT, Yang Y, Mamah C, Aisenberg WH, Saavedra-Rivera PC, Larin BS, Lau AR, Robinson DN, Xiang Y, Wu MN, Sumner CJ, Lloyd TE. TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2. Nat Commun. 2020;11:2679. [PMC free article: PMC7260201] [PubMed: 32471994]
• Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, Cohen P, Khandekar MJ, Boström P, Mepani RJ, Laznik D, Kamenecka TM, Song X, Liedtke W, Mootha VK, Puigserver P, Griffin PR, Clapham DE, Spiegelman BM. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell. 2012;151:96–110. [PMC free article: PMC3477522] [PubMed: 23021218]
• Zimoń M, Baets J, Berciano J, Garcia A, Lopez-Laso E, Merlini L, Hilton-Jones D, McEntagart M, Crosby AH, Barisic N, Boltshauser E, Shaw CE, Landouré G, Ludlow CL, Gaudet R, Houlden H, Reilly MM, Fischbeck KH, Sumner CJ, Timmerman V, Jordanova A, Jonghe PD. Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. Brain. 2010;133:1798–809. [PMC free article: PMC2912694] [PubMed: 20460441]